Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001231209 | SCV001403721 | likely pathogenic | PTEN hamartoma tumor syndrome | 2023-04-14 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Lys128 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17526800, 21828076, 23399955, 25669429). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTEN protein function. ClinVar contains an entry for this variant (Variation ID: 958105). This missense change has been observed in individuals with PTEN-related disorders (PMID: 23470840, 27477328; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 128 of the PTEN protein (p.Lys128Glu). |
| Ambry Genetics | RCV002366034 | SCV002623850 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-08-31 | criteria provided, single submitter | clinical testing | The p.K128E variant (also known as c.382A>G), located in coding exon 5 of the PTEN gene, results from an A to G substitution at nucleotide position 382. The lysine at codon 128 is replaced by glutamic acid, an amino acid with similar properties. This alteration was identified in an individual whose clinical symptoms were consistent with PTEN hamartoma tumor syndrome (PHTS) (Busch RM et al. Genet Med, 2013 Jul;15:548-53). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955). Based on internal structural assessment using published crystal structures, K128E changes ligand binding affinity (Lee CU et al. Angew Chem Int Ed Engl, 2015 Nov;54:13796-800). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |